Cyclic benzimidazole derivatives useful as anti-diabetic agents

Abstract

Novel compounds of the structural formula (I) are activators of AMP-protein kinase and are useful in the treatment, prevention and suppression of diseases mediated by the AMPK-activated protein kinase. The compounds of the present invention are useful in the treatment of Type 2 diabetes, hyperglycemia, metabolic syndrome, obesity, hypercholesterolemia, and hypertension.

What is claimed is: 
     
       1. A compound of structural formula I: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 X is selected from:
 (1) —O—, 
 (2) —O—CH 2 —, 
 (3) —S—, 
 (4) —S—CH 2 —, 
 (5) —NR d —, 
 (6) —NR d —CH 2 —, 
 (7) —CH 2 —, and 
 (8) —CH 2 —CH 2 —, 
 
 
       wherein each CH 2  is unsubstituted or substituted with 1 or 2 substituents selected from: hydroxy, halogen, —C 1-6 alkyl, —CO 2 C 1-6 alkyl, and —COC 1-6 alkyl;
 Y is selected from:
 (1) —C 3-7 cycloalkyl, and 
 (2) —C 3-6 cycloheteroalkyl, 
 
 
       wherein cycloalkyl and cycloheteroalkyl are unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from R b ;
 Z is selected from:
 (1) —(CH 2 ) n CO 2 H, 
 (2) —(CH 2 ) n CO 2 R i , 
 (3) —(CH 2 ) n NHCOR i   
 (4) —(CH 2 ) n SO 2 NHC(O)R i , 
 (5) —(CF 12 ) n NHSO 2 R i , 
 (6) —(CH 2 ) n C(O)NHSO 2 R i , 
 (7) heteroaryl, and 
 (8) —C 2-10 cycloheteroalkyl, 
 
 
       wherein each CH 2  is unsubstituted or substituted with 1 or 2 substituents selected from C 1-6 alkyl, and —OH, and wherein each cycloheteroalkyl and heteroaryl is unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from R c ;
 each R 1  and R 2  is independently selected from:
 (1) halogen, 
 (2) —(CH 2 ) p aryl, 
 (3) biphenyl, and 
 (4) —(CH 2 ) p heteroaryl, 
 
 
       wherein each CH 2  is unsubstituted or substituted with 1 or 2 substituents selected from: halogen, CF 3 , —OH, —NH 2 , —C 1-6 alkyl, —OC 1-6 alkyl, —NHC 1-6 alkyl, and —N(C 1-6 alkyl) 2 , and wherein each biphenyl, aryl and heteroaryl is unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from R a , provided that one and only one of R 1  and R 2  is halogen;
 R 3  and R 4  are each independently selected from:
 (1) hydrogen, 
 (2) halogen, 
 (3) —C 1-6 alkyl, 
 (4) —C 2-6 alkenyl, 
 (5) —C 2-6 alkynyl, 
 (6) —CN, 
 (7) —CF 3 , 
 (8) —OC 1-6 alkyl, 
 (9) —SO 2 C 1-6 alkyl, 
 (10) —SO 2 NHC 1-6 alkyl, and 
 (11) —C(O)NHC 1-6 alkyl, 
 
 
       wherein each alkyl is unsubstituted or substituted with 1, 2 or 3 halogens;
 R 5  is selected from:
 (1) hydrogen, 
 (2) —C 1-6 alkyl, 
 (3) —CH 2 CO 2 H, and 
 (4) —CH 2 CO 2 C 1-6 alkyl; 
 
 each R a  is independently selected from the group consisting of:
 (1) hydrogen, 
 (2) halogen, 
 (3) —(CH 2 ) m OH, 
 (4) —(CH 2 ) m N(R j ) 2 , 
 (5) —(CH 2 ) m CN, 
 (6) —C 1-6 alkyl, 
 (7) —(CH 2 ) m CF 3 , 
 (8) —(CH 2 ) m OCF 3 , 
 (9) —(CF 12 ) m SC 1-6 alkyl, 
 (10) —(CH 2 ) m S(O) 2 C 1-6 alkyl, 
 (11) —(CH 2 ) m S(O) 2 N(C 1-6 alkyl) 2 , 
 (12) —(CH 2 ) m C(O)N(R j ) 2 , 
 (13) —(CH 2 ) m N(R j )C(O)R f , 
 (14) —(CH 2 ) m C(O)R f , 
 (15) —(CH 2 ) m CO 2 R f , 
 (16) —(CH 2 ) m OC(O)R f , 
 (17) —(CH 2 ) m C 3-7 cycloalkyl, 
 (18) —(CH 2 ) m C 3-7 cycloalkenyl, 
 (19) —(CH 2 ) m C 2-6 cycloheteroalkyl, 
 (20) —(CH 2 ) m C 2-6 cycloheteroalkenyl, 
 (21) —(CH 2 ) m aryl, and 
 (22) —(CH 2 ) m heteroaryl, 
 
 
       wherein each CH 2  is unsubstituted or substituted with 1 or 2 substituents selected from: oxo, —(CH 2 ) 0-3 OH, —CN, —C 1-6 alkyl, —OC 1-6 alkyl, halogen, —CH 2 F, —CHF 2 , —CF 3 , and —CO 2 C 1-6 alkyl, and wherein alkyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl and heteroaryl are unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from: oxo, —(CH 2 ) 0-3 OH, —CN, —C 1-6 alkyl, —OC 1-6 alkyl, halogen, —CH 2 F, —CHF 2 , —CF 3 , and —CO 2 C 1-6 alkyl;
 each R b  is independently selected from:
 (1) hydrogen, 
 (2) —C 1-6 alkyl, 
 (3) aryl, 
 (4) heteroaryl, 
 (5) —C 3-6 cycloalkyl, 
 (6) —C 3-6 cycloalkenyl, 
 (7) —C 3-6 cycloheteroalkyl, 
 (8) halogen, 
 (9) —OH, 
 (10) —OC 1-6 alkyl, 
 (11) —CF 3 , 
 (12) —CN, and 
 (13) —SO 2 C 1-6 alkyl, 
 
 
       wherein each alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl and cycloheteroalkyl is unsubstituted or substituted with 1, 2 or 3 halogens;
 each R c  is independently selected from:
 (1) hydrogen, 
 (2) halogen, 
 (3) oxo, 
 (4) —(CH 2 ) r OH, 
 (5) —(CH 2 ) r N(R e ) 2 , 
 (6) —(CH 2 ) r CN, 
 (7) —C 1-6 alkyl, 
 (8) —CF 3 , 
 (9) —(CH 2 ) r C 3-7 cycloalkyl, and 
 (10) —(CH 2 ) r C 2-6 cycloheteroalkyl, 
 
 
       wherein each CH 2  is unsubstituted or substituted with 1 or 2 substituents selected from: oxo, —OH, —CN, —C 1-6 alkyl, —OC 1-6 alkyl, halogen, —CH 2 F, —CHF 2 , and —CF 3 , and wherein alkyl, cycloalkyl, and cycloheteroalkyl are unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from: oxo, —OH, —CN, —C 1-6 alkyl, —OC 1-6 alkyl, halogen, —CH 2 F, —CHF 2 , and —CF 3 ;
 each R d  is independently selected from:
 (1) hydrogen, and 
 (2) C 1-6 alkyl; 
 
 each R e  is independently selected from:
 (1) hydrogen, and 
 (2) C 1-6 alkyl, 
 
 
       wherein alkyl is unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from: —OH, oxo, halogen, C 1-6 alkyl, and —OC 1-6 alkyl;
 each R f  is independently selected from:
 (1) C 1-6 alkyl, 
 (2) C 4-7 cycloalkyl, 
 (3) C 4-7 cycloalkenyl, 
 (4) C 3-7 cycloheteroalkyl, 
 (5) C 3-7 cycloheteroalkenyl, 
 (6) aryl, and 
 (7) heteroaryl, 
 
 
       wherein alkyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl and heteroaryl are unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from: oxo, —OH, —CN, —C 1-6 alkyl, —OC 1-6 alkyl, halogen, —CH 2 F, —CHF 2 , and —CF 3 ;
 each R i  is independently selected from:
 (1) hydrogen, 
 (2) C 1-6 alkyl, 
 (3) C 4-7 cycloalkyl, 
 (4) C 4-7 cycloalkenyl, 
 (5) C 3-7 cycloheteroalkyl, 
 (6) C 3-7 cycloheteroalkenyl, 
 (7) aryl, and 
 (8) heteroaryl, 
 
 
       wherein alkyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl and heteroaryl are unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from: oxo, —OH, —CN, —NH 2 , —C 1-6 alkyl, —OC 1-6 alkyl, halogen, —CH 2 F, —CHF 2 , —CF 3 , —CO 2 H, —CO 2 C 1-6 alkyl, —OCOC 1-6 alkyl, and —OCO 2 C 1-6 alkyl;
 each R j  is independently selected from:
 (1) hydrogen, 
 (2) —C 1-6 alkyl, 
 (3) —C 3-6 cycloalkyl, and 
 (4) —C 3-6 cycloheteroalkyl, 
 
 
       wherein alkyl, cycloalkyl and cycloheteroalkyl are unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from: —OH, oxo, halogen, C 1-6 alkyl, —OC 1-6 alkyl, —NH 2 , —NH(C 1-6 alkyl), and —N(C 1-6 alkyl) 2 ;
 n is 0, 1, 2, 3 or 4; 
 m is 0, 1, 2, 3 or 4; 
 p is 0, 1, 2, or 3; and 
 r is 0, 1 or 2. 
 
     
     
       2. The compound according to  claim 1 , wherein X is selected from:
 (1) —O—, and 
 (2) —O—CH 2 —, 
 
       wherein each CH 2  is unsubstituted or substituted with 1 or 2 substituents selected from: hydroxy, halogen, —C 1-6 alkyl, —CO 2 C 1-6 alkyl, and —COC 1-6 alkyl; or a pharmaceutically acceptable salt thereof. 
     
     
       3. The compound according to  claim 1 , wherein R 1  is independently selected from:
 (1) phenyl, 
 (2) biphenyl, and 
 (3) heteroaryl, 
 
       wherein each phenyl, biphenyl and heteroaryl is unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from R a ; or a pharmaceutically acceptable salt thereof. 
     
     
       4. The compound according to  claim 1 , wherein R 1  is biphenyl, wherein biphenyl is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from R a ; or a pharmaceutically acceptable salt thereof. 
     
     
       5. The compound according to  claim 4 , wherein R 2  is halogen; or a pharmaceutically acceptable salt thereof. 
     
     
       6. The compound according to  claim 1 , wherein Y is —C 3-7 cycloalkyl, wherein cycloalkyl is unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from R b ; or a pharmaceutically acceptable salt thereof. 
     
     
       7. The compound according to  claim 6 , wherein Y is selected from the group consisting of:
 (1) cyclopropyl, 
 (2) cyclobutyl, 
 (3) cyclopentyl, and 
 (4) cyclohexyl, 
 
       wherein each cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl is unsubstituted or substituted with 1, 2 or 3 substituents selected from R b ; or a pharmaceutically acceptable salt thereof. 
     
     
       8. The compound according to  claim 7 , wherein Y is selected from the group consisting of:
 (1) cyclohexyl, and 
 (2) cyclobutyl, 
 
       wherein each cyclohexyl and cyclobutyl is unsubstituted or substituted with 1, 2 or 3 substituents selected from R b ; or a pharmaceutically acceptable salt thereof. 
     
     
       9. The compound according to  claim 1 , wherein RS is hydrogen; 
       or a pharmaceutically acceptable salt thereof. 
     
     
       10. The compound according to  claim 1 , wherein Z is selected from the group consisting of:
 (1) —(CH 2 ) n CO 2 H, 
 (2) —(CH 2 ) n NHCOR i , 
 (3) —(CH 2 ) n NHSO 2 R i , 
 (4) —(CH 2 ) n C(O)NHSO 2 R i , 
 (5) heteroaryl, and 
 (6) —C 2-10 cycloheteroalkyl, 
 
       wherein each CH 2  is unsubstituted or substituted with 1 or 2 substituents selected from C 1-6 alkyl, and —OH, and wherein each cycloheteroalkyl and heteroaryl is unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from R c ; or a pharmaceutically acceptable salt thereof. 
     
     
       11. The compound according to  claim 10 , wherein Z is —CO 2 H; or a pharmaceutically acceptable salt thereof. 
     
     
       12. The compound according to  claim 1 , wherein R 3  and R 4  are each independently selected from:
 (1) hydrogen, and 
 (2) halogen; 
 
       or a pharmaceutically acceptable salt thereof. 
     
     
       13. The compound according to  claim 12 , wherein R 3  is hydrogen or halogen, and R 4  is hydrogen; or a pharmaceutically acceptable salt thereof. 
     
     
       14. The compound according to  claim 1  wherein:
 X is selected from:
 (1) —O—, and 
 (2) —O—CH 2 —; 
 
 Y is selected from the group consisting of:
 (1) cyclopropyl, 
 (2) cyclobutyl, 
 (3) cyclopentyl, and 
 (4) cyclohexyl, 
 
 
       wherein each cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl is unsubstituted or substituted with 1, 2 or 3 substituents selected from R b ;
 Z is —CO 2 H; 
 R 1  is independently selected from:
 (1) phenyl, 
 (2) biphenyl, and 
 (3) heteroaryl, 
 
 
       wherein each phenyl, biphenyl and heteroaryl is unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from R a ;
 R 2  is halogen; 
 R 3  and R 4  are each independently selected from:
 (1) hydrogen, and 
 (2) halogen; and 
 
 R 5  is hydrogen; 
 
       or a pharmaceutically acceptable salt thereof. 
     
     
       15. The compound according to  claim 1  wherein:
 X is selected from:
 (1) —O—, and 
 (2) —O—CH 2 —; 
 
 Y is selected from the group consisting of:
 (1) cyclohexyl, and 
 (2) cyclobutyl, 
 
 
       wherein each cyclohexyl and cyclobutyl is unsubstituted or substituted with 1, 2 or 3 substituents selected from R b ;
 Z is —CO 2 H; 
 R 1  is biphenyl, wherein biphenyl is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from R a ; 
 R 2  is halogen; 
 R 3  is hydrogen or halogen; 
 R 4  is hydrogen; and 
 R 5  is hydrogen; 
 
       or a pharmaceutically acceptable salt thereof. 
     
     
       16. The compound according to  claim 1 , selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof 
     
     
       17. The compound according to  claim 16  which is: 
       
         
           
           
               
               
           
         
       
       or pharmaceutically acceptable salt thereof 
     
     
       18. The compound according to  claim 16  which is: 
       
         
           
           
               
               
           
         
       
       or pharmaceutically acceptable salt thereof 
     
     
       19. The compound according to  claim 16  which is: 
       
         
           
           
               
               
           
         
       
       or pharmaceutically acceptable salt thereof 
     
     
       20. The compound according to  claim 16  which is: 
       
         
           
           
               
               
           
         
       
       or pharmaceutically acceptable salt thereof 
     
     
       21. A composition comprising a compound according to  claim 1  and a pharmaceutically acceptable carrier. 
     
     
       22. A composition comprising a compound according to  claim 1  and a compound selected from simvastatin, ezetimibe, taranabant and sitagliptin; and a pharmaceutically acceptable carrier. 
     
     
       23. A method of treating a disorder, condition or disease responsive to the activation of AMP-activated protein kinase in a patient in need thereof comprising administration of a therapeutically effective amount of a compound according to  claim 1 , wherein the disorder, condition, or disease is Type 2 diabetes.